This application is for competitive renewal of NIDA RO1-11742, and will advance our understanding of the role of Homer in drug^-addiction using transgenic mouse models. During the previous funding period, we generated mouse knockout models for each of the three Homer genes, and in collaboration with Dr. Peter Kalivas of Univ. of South Carolina, determined that Homer 1 and Homer 2 knockout mice exhibit enhanced sensitivity to the acute psychomoter activating effects of cocaine, and self-administer cocaine at low doses that littermate wt mice do not.Furthermore, nai've HI and H2 knockout mice exhibit neurochemical parameters seen in wt mice that are sensitized to cocaine. Accordingly, genetic deletion of Homer 1 or 2 mimics critical aspects of cocaine addiction. This occurs in the absence of exposure to cocaine, and suggests that Homer is critical for adaptations that underlie addiction. Despite these important advances, it remains unknown how changes in Homer protein expression produce the phenotype. Here: Aim 1 will use newly developed transgenic Cre mice to delete Homer 1 and 2 in select populations of cells in the forebrain, and determine in which cells Homers' deletion evokes a cocaine-sensitized phenotype. One hypothesis that will be tested is that Homer's action is critically important in neurons of the striatum/accumbens that express dopamine Dl receptors (D1R). Aim 2 will examine the role of the immediate early gene form of Homer (termed HI a) in cocaine addiction using a newly generated selective genetic knockout model, and a proposed gain of function model. HI a is induced by both cocaine and spatial exploration, and is hypothesized to provide an important contribution to learning hi the cocaine place preference model. Aim 3 will examine the role of Homer interaction with mGluRS in responses to cocaine. mGluRS is known to be essential for behavioral responses to cocaine, and biochemical studies presented in the Preliminary Results reveal that Homer binding to mGluRS is regulated by D1R activity. We are generating mGluRS knock in mice with mutations that selectively disrupt Homer's regulated binding, and will examine the hypothesis that D1R- regulated Homer binding to mGluR is critical for cocaine addiction and Dl-dependent motor responses. Aim 4 will determine the cellular distribution of mGluRS expression that is sufficient to restore responses to cocaine in the mGluR5 knock out. Together, these studies will reveal the cellular bases of Homer's and mGluRS's contribution to cocaine addiction, and test the hypothesis that Homer's interaction with mGluRS is regulatory for Dl-dependent appetitive and motor behaviors.